Amino cyclohexyl ethers



Patented May 23, 1950 AMINO CYCLOHEXYL ETHERS John W. Cusic, Skokie,111., assignor to G. D. Searle & 00., Skokie, 111., a corporation ofIllinois No Drawing. Application February 1, 1947, Serial No. 725,969

. 8 Claims. 1

This invention relates to certain amino-cyclohexyl ethers ofbenzohydrol, its alkyl, alkoxy and halogen substitution products, and of9-fiuorenol. The amino groups, which may be attached to any carbon atomof the cyclohexyl ring other than the one to which the ether linkage isattached, are monoor dialkylamino, N-piperidino, and N-morpholinoradicals. All of the basic ethers contemplated within this invention areincluded in the formula in which Ar and Ar each represent a phenyl, analkyl phenyl, an alkoxy phenyl or a halogenated phenyl group, or takentogether may constitute a 9-fiuoryl group, the CGHIO radical representsa cyclohexane residue to which the oxygen atom and the X group may belinked on any two different carbon atoms, and in which I represents amonoalkylamino, a dialkylamino, a N-piperidino, or a N-morpholino group.These basic ethers generally are oils which are soluble in the commonorganic solvents and insoluble in water, and which in most instances canbe distilled without decomposition in a good vacuum. They form saltswith mineral and with organic acids which in most instances are whitecrystalline solids readily soluble in water. While the valuabletherapeutic properties of these compounds are common to both the freebasic ethers and the salts thereof, the salts constitute a moreconvenient form in which to use these amino ethers because of theirsolid nature and water solubility, and it is to be understood that theappended claims include these ethers both as free bases and in the formof salts thereof.

The ethers of this invention may conveniently be prepared by causing anamino cy'clohexyl halide to react with benzohydrol, its alkyl or alkoxyor halogen substitution products, or 9-fiuorenol in the presence ofsolid sodium hydroxide and at moderately elevated temperatures. Thereaction mixture is poured into water and the amino ether extracted asillustrated in the following examples.

Example 1' ous reaction sets in; when this has mod rated, the mixture iea ed 9 am b t form 2 eral hours. At the end of this time, the mixtureis poured into an excess of dilute hydrochloric acid, and the acidsolution extracted with ether-- to remove neutral by-products. Theaqueous solution is then made strongly alkaline, and the liberated baseextracted with ether, benzene or; other solvent. This solution isdried,the solvent; removed and the residue distilledin a vacuum., Thebenzohydryl 2 dimethylaminocyclohexyl; ether thus obtained boils at 190centigrade at-2j' millimeters pressure. The free base may be 0011 -3verted to a salt by adding an equivalent portion of an alcoholicsolution of the desired acid to'a solution of the base in dry ether.Thus prepared,- the hydrochloride of the ether inthis example; melts atMil-150 C. after recrystallization from-- methyl ethyl ketone.

The reaction illustrated by the above example is quite general in itsapplication to the prepara--' tion of the ethers'of this invention. Bythe use. of substituted benzohydrols, such as the Z-methyl,2,4-dimethyl, 4,4 dimethyl, 2 --m ethy1 5 isopropyl, 2, 3, or 4-chloro,4,4"-dichloro, 2-ethoxy, a-methoxy, or 4,4-dimethoxy derivatives, thecorresponding substituted benzohydryl ethers are obtained in exactly thesame manner as described for benzohydrol in the above example.

Example 2 A mixture of- 35 grams of 2-piperidinocyclo-" hexanol and 21gm. of anhydrous sodium-car-'= bonate are heatedto about C. withthorough agitation, and a solution of 50 gm. of diphenylmethyl bromidein just sufficient benzene to cause it to remain liquid is slowly added.The temperature is gradually raised to C. dur ing the addition, allowingthe benzene to-bqilr-ofl during the evolution of carbon dioxide. Thereaction mixture is maintained at this temperature for several hours,cooled, Washed with water to remove sodium salts, and the oily layerextracted. with ether. The ether solution is extracted with dilutehydrochloric 7 acid, from. which solution the crude free benzohydryl2-piperidino-cyclohexyl ether is liberated by addition'of causticalkali. This is best recovered by extracting with; ether, drying theether solution over solid sodium hydroxide, and subsequently removingthe solvent. It may be further purified by vacuum distillation, boilingat 220 C. at 2 mm. pressure. It may be converted to a salt as describedin-Example'l. The hydrochloride thus prepared melts at 187-189 C.

The reaction illustrated in Example 2 is u t gen a and arbl u d is pare,

V responding cyelohex-anols. When 3- of the aminocyclohexyl etherscontemplated in this invention merely by replacing the diphenylmethylbromide with an equivalent quantity of a substituted diphenylmethylbromide or with 9-bromofluorene, or by replacing the2-piperidino-cyclohexanol with an equivalent quantity of a difierentaminocyqlohexanol.

V 7 Many of the substituted bemohydrols needed to prepare the ethers ofthis invention according to Example 1 are known in the prior art; theyare in general'readily obtained by the reductipn of; the correspondingbenzophenones. Similarly, many of the substituted diphenylmethylbromides contemplated in Example 2-: have been previously described.They are readily available either by bromination of the correspondingdipherryhnethe ane, or by replacement of the hydroxyl group in thecorresponding substituted benzohydrol by eiffects of a subsequentadministration of a dose a bromine atom in any. of several well knownmanners. Y I V z dimethylamino or Z-piperidino cyclohexanol, (or thecorresponding cyclohexyl chlo ride) have-been specified in the aboveexamples, they: may be replaced by a variety of other aminocyclohexanolsoraminocyclohexyl halides as described below to yield the etherspreviously indicated as being contemplated within this invention; Theseaminocyclohexanols are conveniently prepared by: causing achlorocyclohexanolto react with a primary orsecondary amine or withpiperidine ormorpholi-ne, Thus with 2.- chlorocyclohexanol,nonomethylamine will yield the cor-responding 2-monomethylaminooyclohexanol-, dimethylamine will yield 2-dimethylamino eyelohexanol,piperidine will yield Z-piper-idino cyclohexanol, and morpholine willyield Z-morpholino cyclohexanol. Similarly higher alkyt amines, such asmonoor di-ethyl, propyhbuty-l, or hexyl amines will yield the coror 4-ohlorocyclohexanol is used in place of- 2 -chlorocyclohexanol', thecorresponding 3- or- -ami-nooyclohexanols will likewise be formed. Anyof these am i -nocyelohexanols'ma be used; in molecula rly equivalentquantities in place of the 2- dimethylam-i-no cyclohex-anol specified.in Example 2- to'produce the aminocyclohexyl ethers of this invention.Further, these 'aminocyclohexanols may be converted to thecorrespondingam-inooyclohexyl chlorides by the action of thionylchloride in an inert solvent; Any of these 'aminocyclohexyl chloridesmay be successfullysubstituted for theiz-dimethylamino cyelohexylchloride specified in Example 1 to yield the-'aminocyciohexyl ethers ofthis invention. 7

The amingcyclohexyl ethers of this invention are useful therapeutics,particularly as spasmolytic and; as anti-histamine agents. When testedon isolatedsmo th-muscle strips'for their ability to reiax' spasmsinduced either by'acetylcholine 'orbybalrium ions, representative compoundsfrom the ethers of this invention have exerted a powerful relaxingefl'ect, Thus, for instance, the 2-piperidinocyclohexyl ether oibenzohydrol produced; relaxation of spasms inof the sensitizing proteinwhich produces uniformly fatal; doses in untreated animals.

As will be expected, the aminocyclohexyl ethers of this invention differamong themselves not only in potency as therapeutic agents, but also inacutetoxicity. This toxic level is sufficier tly high, 'lgiowever, thata desirably wide margin of safety exists between efiective and toxicdoses, so that these compounds may be safely and efiectively used as;therapeutic agents.

Ijhe invention is defined by the appended claims.

I claim: l. Amino-cyclohexyl-ethers of the formula n. which Ar. and. ArachreP-r s nt a r d-ml chosen from the group consisting of phenyl,alkyl-substituted phenyl, alkoxy-substituted phenyl, andhalogen-substituted phenyl; in which the Cal-I10 is' acycl-ohexaneresidue to which the oxygen atom and the X group may beattached on ny we d fierent c rbon atoms..:, and whi ep esents a. rad alch res rom t e gr u 7' alk lam mr mples. and b -mmholin qycl n xr ethersi. the formula V oH-o-cr -om-X Ar! 0 om,

GEM-CH2 v which Ar and, each repre n a d ca hosen fr m th ro p 99. .1.ins. o he y alky n wh h t e era is acy lqb ra e residue to wh ch th oxseaetpm a d h .X ou

r b tached Q 'anr two dif rent car on toms;

duced by either of the above mentioned a ents with approximately thesame potency, which potency is comparable ip magnitude with that dis:played by some of the most powerful synthetic spasmoly-tic agentsheretofore disclosed.

Similarly the aminocyclohexyl ethers 0; this n en on. r pp ten a h st mia onist and antieallergic substances. Animals treated with one of theseethers prior to exposure to an din. wh ch re e ents a ra l ra e e leaitem the emu q s in qfmeeqallw amina dial srle n which s smears. rad calcho n from he 5. Benzohydryl 2 dimethylaminocyclohexyl 8. Aminocyclohexyl ethers of the formula ether, whose formula is G O\ 0H-0-o11o11, o11 x in which X represents a. radical chosen from the groupconsisting of monoalkylammo, dialkyla- 6. Benzohydryl2-piper1d1nocyc1ohexy1 ether, mine Nmmerldmo, and N morpholmo whoseformula 15 JOHN W CUSIC.

CHr-CH: REFERENCES CITED C The following references are of record in theO e g on, clan-0 15 file of this potent:

CHrClz UNITED STATES PATENTS 7. Amino cyclohexyl ethers of the formulaNumber Name Date M 1,978,539 Klarer et a1 Oct. 30, 1934 C 2,397,799Martin Apr. 2, 1946 2,421,714 Rieveschl June a, 1947 Ar Hr-CHrHa 2,437,?11 Rieveschl Mar. 16, 1948 in which Ar and Ar each represent a radical2,443,796 Martin et a] June 1943 chosen from the group consisting ofphenyl, 2.1- OTHER REFERENCES kyl-substituted phenyl, alkoxy-substitutedphenyl, and halogen-substituted. phenyl; and in which 25 X represents aradical chosen from the group consisting of monoalkylamino,dialkylamino, N-piperidino, and N-morpholino.

Loew: J. Pharmacol et 91, vol. 83, Feb. 1945, pp. -129.

1. AMINO CYCLOHEXYL ETHERS OF THE FORMULA